N,n&#39;-di-(pyrmidyl-(4)-aminoalkyl)-diazacycloalkanes



United States Patent 3,503,963 N,N-DI-[PYRMIDYL-(4)-AMINOALKYL]- DIAZACYCLOALKANES Ernst Schweizer, Basel, Switzerland, assignor to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Continuation-impart of application Ser. No.

577,600, Sept. 7, 1966. This application Nov. 30, 1966, Ser. No. 597,870 Claims priority, application Switzerland, Oct. 22, 1965, 14,630/65; Aug. 5, 1966, 11,330/66 Int. Cl. C07d 51/70 US. Cl. 260-239.65 9 Claims ABSTRACT OF THE DISCLOSURE N,N' di [pyrimidyl (4)-aminoalkyl]-diazacycl0- alkanes in which the alklene radicals separate the nitrogen atoms bound to them by at least 2 carbon atoms in each case, and their N-oxides. The compounds are useful as antibacterial, tumor-inhibiting and anti-inflammatory agents.

This is a continuation-in-part application of our copending application Ser. No. 577,600, filed Sept. 7, 1966 now abandoned.

The present invention relates to new pyrimidines and their salts. Especially it concerns N,N'-di-[pyrimidyl-(4)- aminoalkyl]-diazacycloalkanes in which the alkylene radicals separate the nitrogen atoms bound to them by at least 2 carbon atoms in each case, and their N-oxides.

The amino groups in the new compounds may be further substituted. Thus, the amino groups may also be tertiary and may be substituted for instance by lower alkyls such as methyl or ethyl or linear or branched propyl, butyl or pentyl residues linked in any desired position; or aralkyl radicals such as phenyl-lower alkyls, for example benzyl or phenylethyl radicals.

Furthermore, the pyrimidyl residues may likewise be substituted, for example in the 2-position by halogen; by lower aliphatic hydrocarbon residues, especially lower 'alkenyl or preferably lower alkyl radicals; by lower aliphatic hydrocarbon residues containing an etherified hydroxyl group, for example of the kind mentioned above, such as lower alkoxy-lower alkyl or lower alkenyloxylower groups; by hydroxyl groups substituted by lower aliphatic hydrocarbon residues, for example of the kind mentioned above, being for example lower alkenyloxy or preferably lower alkoxy or lower alkoxy-lower alkoxy groups; or by corresponding residues in which oxygen atoms are replaced by sulphur atoms; or by free hydroxyl or mercapto groups or by amino groups. The lower alkyl radicals have also in the ether residues primarily the meaning given them above and are in the first place methyl, ethyl or propyl radicals. As lower alkenyl residues, also in the ether residues, there may be mentioned above all allyl radicals or methallyl or crotonyl radicals.

The lower alkoxy radicals in the lower alkoxy-lower alkyl residues are, for example, those mentioned above. The alkylene radicals which connect the oxygen atom with the pyrimidine nucleus are preferably alkylenes containing 1 to 5, especially 1 to 3, carbon atoms, being for example methylene residues, or ethylene, propylene, butylene or pentylene residues bound in any desired position. Lower alkoxy-lower alkyl radicals are especially residues of the formula RO(CH where R represents an alkyl radical containing 1 to 3 carbon atoms and 11:1, 2 or 3.

The alkoxy groups present in the lower alkoxy-lower alkoxy residues are, for example, those mentioned above.

The alkylene radical connecting these alkoxy groups with the oxygen atom on the pyrimidine nucleus contains between the alkoxy group and the oxygen atom mentioned at least two carbon atoms and contains preferably 2 to 5 carbon atoms; more especially it is a 1,2-ethylene group or a 1,2- or 2,3- or 1,3-propylene group, or linear or branched butylene or pentylene group bound in any desired position which separates the vicinal oxygen atoms by at least two carbon atoms. In these residues the oxygen atoms may be replaced by sulfur.

Halogen atoms are more especially bromine, and above all chlorine.

Amino groups as Z-substituents of the pyrimidine ring may be, for example, primary, secondary or tertiary. Suitable substituents are, for example: Lower hydrocarbon residues of aliphatic character, whose carbon chain may be interrupted by hetero atoms such as oxygen, sulfur or nitrogen and/or which may be substituted by free hydroxyl or amino groups. Lower hydrocarbon residues of aliphatic character are above all alkyl, alkenyl, cycloalkyl or cycloalkenyl radicals, cycloakyl-alkyl or -alkenyl radicals, cycloalkenyl-alkyl or -alkenyl radicals containing up to 8 carbon atoms. Residues of this kind that are interrupted by hetero atoms are above all oxaalkyl, azaalkyl, oxaalkylene, azaalkylene or oxacycloalkyl-alkyl radicals. Lower hydrocarbon residues interrupted by hetero atoms include above all also aminoalkyl radicals in which the amino group is substituted as indicated above and described below. There may be specially mentioned methyl, ethyl, allyl, propyl, isopropyl residues; linear or branched butyl, pentyl, hexyl or heptyl residues bound in any desired position; 3-oxabutyl, 3-oxapentyl, 3-oxaheptyl, 2-hydroxyethyl, 3-hydroxypropyl, butylene-( 1,4), pentylene-(1,5), hexylene-( 1,5), hexylene-(1,6), hexylcue-(2,5), heptylene-(1,7), heptylene-(2,7), heptylene- (2,6), 3-oxa-pentylene-(l,5), 3-aza-pentylene-(1,5), 3- lower alkyl-3-aza-pentylene-(1,5) such as 3-methyl-3-azapentylene-( 1,5), 3-(hydroxy-lower alkyl)-3-aza-pentylene-(l,5) such as 3-hydroxyethyl3-aza-pentylene-( 1,5), 3-oxa-hexylene-(1,6) or 3-aza-hexylene-(1,6), cyclopentyl or cyclohexyl residues, or cyclopentylor cyclohexyl-methyl or -ethyl residues.

The amino group is preferably secondary, being especially a lower alkyl-amino group, for example, a methylamino, ethylamino or above all a propyl'amino, butylamino or pentylamino group in which the alkyl radicals are preferably not of primary nature, for example, an isopropylamino or secondary butylamino-group. Of special advantage are, however, tertiary amino groups, especially di-lower alkyl-amino groups such as dimethylamino, diethylamino, N-methyl-N-ethylamino, dipropylamino, diisopropylamino, dibutyl-amino, di-secondary butylamino or di-amylamino groups, or pyrrolidino, piperidino, piperazino, N-lower alkylor N-hydroxy-lower alkyl piperazino or morpholino groups. The amino group on the pyrimidine nucleus in the 2-position may also be with advantage a loweralkyl amino group substituted by one of the afore-mentioned secondary or tertiary amino groups, such as monoor di-lower alkylamino, pyrrolidino, piperidino, piperazino, N-lower alkylpiperazino or N-hydroxylower alkyl-piperazino or morpholino-lower alkylamino group.

The pyrimidine nucleus may also be substituted in position 5 and/ or 6, above all by one of the substituents indicated above for position 2. Lower alkyl radicals in positions 5 and 6 may together form an alkylene radical, for example, a butylene-( 1,4) radical.

The diazacycloalkane ring, in which the alkylene radicals separate the nitrogen atoms by at least 2 carbon atoms, thus contains at least 6 cyclic members, and preferably at most 8 cyclic members. The alkylene radicals are above all linear or branched alkylene radicals each containing at most 6 carbon atoms, for example butylene- (2,4), butylene-( 1,4), pentylene-(1,5), pentylene-(2,5),

3 4 hexylene-(2,6) or 'hexylene-(3,6) or above all an ethylpecially methyl; the residues R and R represents above ene-(l,2) residue and in the first place propylene-(1,3) al hydrogen or in the second place lower alkyl or lower or propylene-(2,3) or propylene-(1,2). In the first place alkoxy-lower alkyl residues, especially those of the kind the diazacycloalkane ring is a piperazine ring which may indicated above for R and R and the residues Alk and be substituted by lower alkyl radicals, above all by meth- Alk are lower alkylene-(l, 1) residues containing 2 yl groups, and is especially the piperazine ring. to 6 carbon atoms, above all 2 to 4 carbon atoms, and in The alkylene radicals that separate the diazacycloalthe first place propylene-(1, l) radicals (primarily prokane ring from the pyrimidyl-4-amino groups by at least pylene(1,3) radicals and especially butylene-(1,4) rad- 2 carbon atoms contain predominantly 2 to 6 carbon icals.

atoms and are, for example, butylene-(2,4), butylene- Special mention deserve compounds of the formula (1,4), pentylene-(1,5), pentylene-(2,5), hexylene-(1,6), 10 II or hexylene-(2,6), but preferably ethylene-( 1,2), and pri- NH-Alk-N N-A1k-NH marily propylene-(1,3), propylene-(2,3) or propylenel (1.2). N The two pyrimidylaminoalkyl residues in the new com- I l I Pounds may be identical or diiferent. 1 2- 1' The new compounds possess valuable pharmacological N properties. More especially, they act against bacteria, Where 1" and 1' represent fme amino groups of PY such as tubercle bacilli, above all against protozoa, esl'olldino, Plpefldlllo, morphollno, P P

pecially plasmodia, for example, in the mouse, and against y -p p Y Y- alkyl-plpel'allno piroplasms such as babesia, babesiellae and theileriae. p and above all mono- (ll-lower alkylamlflo They also act against plasmodia that resist known antig p for example as indicated above, nd especially malarial medicaments. The new compounds may therediethylamino or preferably dimethylamino groups; R fore be used pharmacologically on animals or as medicand R represent hydrogen or lower alkyl, such as aments, for example for treating malaria, babesiosis, propyl, ethyl or especially methyl, :and Alk" and Olk theileriosis, anaplasmosis and other infections. They may 0 are pr pyl n P py -(2,3), ethylene-(1,2) or also be used as animal feedstuffs or as additives to animal primarily propylene-(1,3) and butylene-(1,4). feedstulfs. Furthermore, they have a tumour inhibitory Particularly valuable anti-malarial medicaments and activity and, for example in the rat, the new compounds antiphlogistics are N,N-di-['y-(6-methylamino-2-methyldisplay an anti-inflammatory action. They may thus be pyrimidyl-4-amino)-propyl]-piperazine, further N,N-diused pharmacologically on animals or medicinally as anti- ['y-(6-amino 2 methyl-pyrimidyl 4 amino)-propyl]- phlogistics. Moreover, they are valuable intermediates. piperazine and in the first place N,N'-di-['y-(6-dimethyl- Particularly potent, above all in their action against amino 2-methyl-pyrimidyl-4-amino)-propyl]-piperazine plasmodia and babesia and as anti-inflammatory subof the Formula III III 1fHOHzCHz-CH2N\ E-CHz-CHrCHz-NH N l N l CH3-kN/N(CH3)2 l kN 3 stances, are those compounds in which at least one of the pyrimidine rings contains in position 2 and/or 6 a free amino group or, for example, one substituted as indicated above, and in the first place compounds of the which for example develops a pronounced antimalerial action in the mouse on subcutaneous administration in doses of 20-40 mg. per kg. bodyweight and which displays in the rat in the kaolin and in the pleuritis test in formula I doses of 30-50 mg./ kg. subcutaneously and 1n the foreign 1 1 body granuloma in doses of 10-3O mg./ kg. subcutaneousl ly a distinct anti-inflammatory effect, and, on account N R; N 113' of its anti-malarial effect N,N'-di-['y-(6-dimethylaminol l I 2- methyl-pyrimidyl-4-amino)-butyl]-piperazine of the for- R2\\N/ R1 R2 1 mula NH-CHg-CHz-CHz-CHz-U-CHz-CHz-CH2CH2-iNH N l q CH -kN N(CH3)2 CH3 \N/ N(OI'I3)2 where at least one of the residues R R and R R is Likewise SpeClallY Valuable, though less 0 than th a free amino group or a substituted amino group, above above yp of P l and are those of t se all one of those speciall mentioned above, and particuformulae in WhlCh the resldues which in these formulae larly a monoor di-lower alkylamino, pyrrolidino, piperrepresent amino groups, p hydrogen a lower idino, morpholino, piperazine or N-lower alkyl-pipery or lower alkoxy-lower alkyl p, r ex mple as azino or hydroxy-lower alkyl-piperazino group, for exlndl at d above. 0 ample as indicated above, and especially a diethylamino T n w c mp unds are tain d 1n the usual mangroup or preferably a dimethylamino group, whereas the net; v g y, all y iazacyothers of these residues may represent hydrogen or prefcloalkane in which the alkylene chains separate their suberably a loweralkylor lower alkoxy-lower alkyl radical, stituents by at least 2 carbon atoms in each case, is reabove all one of those specially mentioned above, esacted with 2 molecules of a 4-halogeno-pyrimidine. A

pecially propyl, ethyl, methoxyethyl, ethoxyethyl, or eshalogen atom is primarily a chlorine or bromine atom.

Furthermore, the new compounds are also obtained when in a derivative of an N,N'-di-[pyrimidyl-(4)-aminoalkyl]-diazacycloalkane, in which the alkylene chains separate the nitrogen atoms in each case by at least 2 carbon atoms, and which differs from this diazacycloalkane by the fact that in it at least one of the alkylene chains contains a residue which can be selectively exchanged for hydrogen, the residues replaceable by hydrogen are so replaced. Such residues are above all oxo groups attached to a carbon atom linked with nitrogen and which can be replaced by hydrogen by the usual amide reducing agents, above all lithium-aluminium hydride and similar amide reducing agents, without a substantial reduction taking place in the pyrimidine rings. An advantageously used starting material is a suitable N,N'-di-[w-(pyrimidyl-(4)=amino)-wor -a-oxoalkyl]-diazacycloalkane.

Substituents in resulting compounds can be converted in the usual manner within the framework of the final process products as defined. More especially halogen atoms, in positions 2 and/or 6 of the pyrimidine rings, may be exchanged for amino groups, for example by treatment with ammonia or a primary or secondary amine.

For the manufacture of 2-amino-pyrimidyl-(4) compounds, especially of compounds of the Formula I where the residues R and R are amino groups, it is most advantageous to start from a 2,4-dihalogeno-pyrimide, especially from a compound of the formula will and from N,N'-di-aminoalkyl-diazacycloalkanes, especially those of the formula where Hal are halogen atoms and R and Alk have the above meanings, and after having reacted the halogen atom in position 4 the halogen atom in position 2 is exchanged for an amino group R or R For the manufacture of 6-amino-pyrimidyl-(4) compounds, especially the compounds of the Formula I in which R and R are amino groups, it is advantageous to start directly from the 6-amino-4-halogeno-pyrimidine compounds.

The afore-mentioned reactions are carried out in the usual manner, in the presence or absence of diluents and/ or condensing agents and/or catalysts, at room temperature or with cooling or heating, if required under superatmospheric pressure and/or in an inert gas.

Depending on the reaction conditions used the new compounds are obtained in the free form or in the form of their salts. The bases form therapeutically acceptable salts on treatment with acids, for example therapeutically acceptable acids such as hydrohalic acids, sulphuric or phosphoric acids, nitric or perchloric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulphonic acids, such as formic, acetic, propionic, oxalic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, hydroxymaleic, dihydroxymaleic or pyruvic acid; phenylacetic, benzoic, para-aminobenzoic, anthranilic, para-hydroxybenzoic, salicyclic, embonic, or para-arminosalicyclic acid; methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, "ethylenesulphonic acid; toluenesulphonic, naphthalene sulphonic acids or sulphanilic acid; methionine, trypt'ophan, lysine or arginine. Resulting salts can be converted into the free compounds.

The salts may also be used for purifying the free compounds. In view of the close relationship between the new compounds in the free form and in the form of their salts, what has been said above with reference to the free compounds concerns also the corresponding salts wherever this is possible and useful.

The invention includes also any variant of the process in which an intermediate obtained at any stage of the process is used as starting material and any remaining step/steps is/are carried out, or a starting material is formed under the reaction conditions or is used in the form of a salt thereof, as well as the new starting materials. It is advantageous to use starting materials and reaction conditions that give rise to the final products specially mentioned above.

The resulting diazacycloalkane compounds can be converted into their N-oxides in the usual manner, for example by means of hydrogen peroxide or organic peracids, such as perbenzoic or peracetic acid.

A resulting racemic compound can be split into its optical antipodes in the usual manner.

The starting materials are known or are prepared by analogous methods. New starting materials are likewise included in the present invention. Starting materials that differ from the final products by the presence of a residue exchangeable for hydrogen in at least one of the alkylene radicals, especially the 0x0 compounds, likewise have the actions described above for the final products and are included in the present invention; they are obtained by one of the known relevant methods referred to above, for example from corresponding starting materials containing an oxo group.

The new final products and their salts can be used as medicaments, for example in the form of pharmaceutical preparations containing the new compounds or their salts in conjunction or admixture with an organic or inorganic, solid or liquid pharmaceutical excipient suitable for enteral or parenteral administration. Suitable excipients are substances that do not react with the new compounds, for example water, lactose, starches, magnesium stearate, talcum, vegetable oils, benzyl alcohols, gums, polyalkyleneglycols, cholesterol or other known medicinal excipients. The pharmaceutical preparations may be, for example, tablets or dragees, or in liquid form solutions, suspensions or emulsions. They may be sterilized and/or may contain auxiliaries, such as preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure or buffers. They may also contain other therapeutically useful substances. The following examples illustrate the invention.

EXAMPLE 1 A mixture of 14.2 g. of 2,6-dimethyl-4-chloropyrimidine and 10 g. of N,N'-di-'y-aminopropyl-piperazine is heated for 2 hours at C. The resulting product is dissolved in dilute acetic acid, and the solution is treated with active carbon and then rendered alkaline. The precipitated N,N' di y-(2,6-dimethyl-pyrimidyl-4-amino)-propyl]- piperazine of the formula IIIH-CH2-CH2-CHz-Nk N-CHz-OHz-CHz-lTIH N l i II is suctioned off and recrystallized from aqueous methanol; it melts at 146 to 148 C.

EXAMPLE 2 A mixture of 17.1 g. of 2-methyl-6-dimethylarnino- 4-chloropyrimidine, 10 g. of N,N-di-'y-aminopropylpiperazine and 50 cc. of sulpholane is heated for 4 hours at C., allowed to cool, poured into water, and the solution is rendered weakly alkaline. The precipitate is suctioned olf and recrystallized from aqueous methanol. The resulting N,N'-di-['y-(2-methyl-6-dimethyl- 7 amino pyrimidyl 4 amino)-propyl]-piperazine of the formula idine and g. of N,N'-di-' -aminopropyl-piperazine are mixed together with 75 g. of phenol and 250 mg. of ammonium chloride and the Whole is stirred and heated for 4 hours at 180 to 190 C. The cooled batch is stirred into 1 litre of 2 N-sodium hydroxide solution, and the precipitate is suctioned off and recrystallized from dimethylformamide, to yield N,N'-di-['y-(2-methyl-6- methylamino pyrimidyl-4-amino)-propyl]-piperazine of the formula N l CH -kN NH-CH;

melting at 204 to 206 C.

EXAMPLE 4 A mixture of 14.3 g. of 2-methyl-6-amino-4-chloropyrimidine, 10 g. of N,N'-di-'y-aminopropyl-piperazine, 75 g. of phenol and 250 mg. of ammonium chloride is heated for 4 hours at 180 to 190 C., allowed to cool and then poured into 1 litre of 2 N-sodium hydroxide solution. The precipitate is suctioned oif and recrystallized from methanol, to yield N,N-di-[y-(2-inethyl-6-aminopyrimidyl-4-amino)-propyl]-piperazine of the formula melting at 200 to 202 C.

EXAMPLE 5 18.8 g. of 2-methoxymethyl-6-methylamino-4-chloroi NHCH;

8 the mixture is then cooled to C. and stirred into 500 :ml. of 2 N sodium hydroxide solution. The precipitating 10 N,N-di-[' -(2-methoxymethyl-6-methylamino pyrimidyl-4-amino)-propyl]-piperazine of the formula K CHSNH \\N (Jr-noon.

melts at 178-182" C.

EXAMPLE 6 A mixture of 16.3 g. of 2-dimethylamino-6-methyl-4- chloropyrimidine, 10 g. of N,N'-di-'y-amino-propyl-piperazine, 30 g. of phenol and 250 mg. of ammonium chloride is heated for 4 hours at C. The isolation of the base is carried out as described in Example 4. The base is dissolved in ethanol. By the addition of ethanolic byi NH-CH;

drochloric acid the tetrahydrochloride of N,N'-di-['y-(2- dimethylamino-6-methylpyrimidyl 4 amino)-propyl] 40 piperazine of the formula )L-CHr-CHn-CHz-IIIH 41101 is obtained which, when recrystallized from ethanol, melts at 300 C.

EXAMPLE 7 20 g. of N.N'-di-y-aminopropyl-piperazine and 28 ml. of triethylamine are dissolved in 60 ml. of methanol. A solution of 2-methyl-4,6-dichloropyrimidine is added dropwise at 60 C. The mixture is heated for 8 hours under reflux, the methanol distilled off and the residue treated with 2 N sodium hydroxide solution. N,N'-di-['y- (2-methyl-6-chloropyrimidyl-4-amino) propyl] -piperazine of the formula pyrimidine, 10 g. of N,N'-di y-aminopropyl-piperazine is filtered with suction and recrystallized from a mixture and 23.5 g. of phenol are heated for 4 hours at C.; 75 of methanol and water; it melts at 157-160 C.

5.6 g. of the substance described in Example 7 are 43 6 v o g. of 2,4,5,6-tetrachloropyr1m1d1ne are dissolved heated at 190 C. with 50 ml. of morphohne for 4 hours. in 300 mL of ethanol and a solution of 20 of The residue is treated with 2 N sodium hydroxide solu- -ammopropyl-plperazlne in 100 ml. of ethanol 1s added non and d1 [7 (2 methyl 6 morpholmo'pynml dropwise at room temperature. After stirring for 2 hours dyl-4-amino) -propyl]-piperazine of the formula NHCHzCH2-CH2N\ N-OHz-CHz-OHz-NH l F-s W a N NJ CHa l N N is filtered with suction and recrystallized from dimethylthe precipitated N,N'-di-[' -(2,5,6-trichloropyrimidyl-4- formamide; it melts at 178-180 C. am n )-p py ]-p p ne f the formula EXAMPLE 9 NHCHzCHz CH2N' NCH2CHz-CHzNI-I l 1 By an analogous reaction to that described in Example N 01 8 with N-methyl-piperazine there is obtained N,N'-di-['yl N {Z-methyl 6 methylpiperazino) pyrimidyl-4-amino} C1 kN/ 1 O1 J propyl]-pipe-razine of the formula It IS relirystanlzed r Water and melts at 68-80 is filtered with suction and recrystallized from dimethyl- EXAMPLE 10, formarnide; it melts at 280 C. with decomposition. By an analogous reaction to that described in Example 8 with piperidine there is obtained N,N'-di-['y-(2-methyl- 6-piperidino pyrimidyl 4 amino) -propyl]-piperazine 5 of the formula EXAMPLE 13 19.6 g. of the compound described in Example 12 I are heated with 200 ml. of a saturated methanolic NEFCHPCHrCHH dimethylamine solution for -8 hours at 120 C. in an autoclave, the methanol is distilled off and the residue N N treated with water. The precipitating N,N-do-['y-{2,6-di- L 1 J (dimethylamino) 5 chloropyrimidyl 4 amino}- CHF propyl]-piperazine hexahydrochloride of the formula is filtered with suction and recrystallized from dimethyl- It melts at 154156 C. after recrystallization from diformamide; it melts at 253-255 C.

methylformamide. EXAMPLE 14 EXAMPLE 11 v By an analogous reaction to that described in Example By an analogous reacttion to that described in Example 13 with morpholine there is obtained N,N'-di-['y-(2',6-

8 with pyrrolidine there is obtained N,N'-di-[ y-(2-methyldimoropholino 5 chloropyrimidyl 4 amino)-propyl]- piperazine of the formula N l 01 o1] Nl lN W O N la 0 N 1 N 6-pyrrolidino-pyrimidyl 4 amino)-pr0pyl]-piperazine which is recrystallized from methanol; it melts at 207- of the formula 210 C.

EXAMPLE 15 17.29 g. of N,N-di- 3-aminoethyl-piperazine and 28 N 7 ml. of triethylamine are dissolved in ml. of methanol. l A solution of 32.6 g. of 2-methyl-4,6-dichloropyrimidine GH -k N N -CH; in ml. of methanol is added dropwise. After heating N N for 8 hours under reflux, the methanol is distilled off, which melts at -147 C. after recrystallization from the residue is dissolved in 200 ml. of ethanol, treated dimethylformamide 75 with active carbon, filtered off and the hot filtrate treated 1 1 with hot water until it becomes turbid. On cooling, N,N'- di-[fi-(Z methyl 6 chloropyrimidyl 4 amino)- ethyl] -piperazine of the formula IIIH-CHz-CHz-N N-CHz-GHz-IITH 01 NloHg crystallizes out; it melts at 166-169 C.

EXAMPLE 16 l l OWN ago...

precipitates; it melts at 168-170 C.

EXAMPLE 17 By an analogous reaction to that described in Example 16 with morpholine there is obtained N,N'-di- [fl-(Z- methyl 6 morpholino-pyrimidyl 4 amino)-ethyl]- piperazine of the formula It is recrystallized from dimethylformamide and melts at 227-229 C.

EXAMPLE 18 A mixture of 28.4 g. of 2,6-dimethy1-4-chloropyrimidine, 17.2 g. of N,N'-di-fi-aminoethy1-piperazine, 75 g. of phenol and 250 mg. of ammonium chloride is heated for 4 hours at 170 C. and then stirred into 1 litre of 2 N sodium hydroxide solution. N,N'-di- [pt-(2,6- dimethyl-pyrimidyl-4-amino)-ethyl]-piperazine of the formula NH-CHa-CHr-N N-CHz-CHr-IITH 1k: CH1}...

is filtered with suction and recrystallized from a mixture of methanol and water; it melts at 151-153 C.

EXAMPLE 19 31.4 g. of 2-methyl-6-methylamino-4-chloropyrimidine and 17.2 g. of N,N'di-/8-aminoethyl-piperazine are mixed together with 31.3 g. of phenol and 200 mg. of ammonium chloride and heated for 4 hours at 185 C. The cooled mixture is stirred into 400 ml. of 2 N sodium hydroxide solution. N,N'-di[fi-(2-methyl 6 methylamino-pyrimidyl 4 amino)-ethyl]-piperazine of the formula precipitates and is filtered with suction; it melts at 225228 C.

EXAMPLE 20 A mixture of 34.3 g. of 2-methyl-6-dimethyl-amino- 4-chloropyrimidine, 17.2 g. of N,N-di- 8-amino-ethylpiperazine and 47 -g. of phenol is heated for 4 hours at 190 C. The reaction mixture is worked up as described in Example 19. N.N'-di-[[3-(2-methyl-6-dimethyla1ninopyrimidyl-4-amino)-ethyl]-piperazine of the formula l l K r-k N 3): a)2 s is recrystallized from a mixture of methanol and water and melts at 1l7l20 C.

EXAMPLE 21 A mixture of 14.2 of 2,6-dimethyl-4-chloropyrimidine, 11.4 g. of N,N'-di-6-aminobutyl-piperazine, 37.5 g. of phenol and 200 mg. of ammonium chloride is heated for 4 hours at 170 C. and N,N-di-[6-(2,6-dimethylpyrimidyl-4-amino)-butyl]-piperazine of the formula CH l is isolated by treatment with 2 N sodium hydroxide solution. The dihydrochloride melts at 268271 C.

'EXAMPLE 22 By reacting 6.8 g. of 2-methyl-6-dimethylamino-4- chloropyrimidine, 4.6 g. of N,N-di-6-aminobutyl-piperazine and 11.7 g. of phenol in the way described in Example 21 there is obtained N,N-di-[6-(2-methyl-6-dimethylamino-pyrimidyl-4-amino)-buty1]-piperazine of the formula g N CHz-kN (CH3)2N NLCHa which after recrystallization from a mixture of methanol and water melts at -112 C.

EXAMPLE 23 N,N' di [6 (2 methyl 6 chloro pyri-midyl 4- amino)-butyl]-piperazine of the formula i a)a C1 CH is obtained by reacting 32.6 g. of 2-methyl-4,6-dichloropyrimidine and 22.8 g. of N,N'-di-fi-aminobutyl-piperazine in ml. of methanol in the presence of 28 ml. of triethylamine by heating under reflux for 8 hours. The

13' methanol is distilled off and the compound recrystallized from a mixture of methanol and water; it melts at 145- EXAMPLE 24 14.2 g. of 2,6-dimethyl-4-chloropyrimidine, 11.4 g. of N,N'-di-' -aminopropyl-2,S-dimethylpiperazine, 35 g. of phenol and 200 mg. of ammonium chloride are heated for 4 hours at 190 C. N,N'-di-['y-(2,6-dimethyl-pyrirnidyl-4- amino)-propyl]-2,5-dimethylpiperazine of the formula is isolated by treatment with 500 ml. of 2 N sodium hydroxide solution; the product melts at 183-185 C.

EXAMPLE 25 By reacting 15.7 g, of 2-methyl-6-methylamino-4- chloropyrimidine, 11.4 g. of N,N-di-' -amino-propyl-Z,5- dimethylpiperazine, 35 g. of phenol and 200 mg. of ammonium chloride in the manner described in Example 24 there is obtained N,N'-di-[' -(2-methyl-6methylaminopyrimidyl-4-amino)-propyl]-2,S-dimethylpiperazine of the formula CH N [[t is recrystallized from a mixture of methanol and water and melts at 17017 5 C.

EXAMPLE 26 N,N' di ['y (2 methyl 6 dimethylamino pyrimidyl-4-amino-propyl]-2,S-dimethylpiperazine of the formula WI CH (II-bk N( 3)2 lTTH-CHz-CHz-CHz-N N-CHz-CHa-CHz-ITIH N CHg-kN Cl NLCHs is formed when 16.3 g. of 2-methyl-4,6-dichloropyrimidine and 11.4 g. of N,N'-di-'y-aminopropyl-2,5-dimethylpiperazine are reacted in 100 ml. of methanol in the presence of 14 ml. of triethylamine. The compound is recrystallized from a mixture of methanol and water and melts at 170'-172 C.

14 EXAMPLE 2s A mixture of 11.4 g. of Z-methyl-6-di-methyl-amino-4- chloropyrimidine, 8.7 g. of N,N'-di-' -amino-fl-dimethylpropyl-piperazine, 15.7 g. of phenol and mg. of ammonium chloride is heated for 3 hours at C.; after cooling, the reaction mixture is stirred into 250 ml. of 2 N sodium hydroxide solution, N,N'-di-[7-(2-1116thYl-6-dimethylamino pyrimidyl 4 amino) p dimethyl-' propyl]-piperazine of the formula precipitating. After recrystallization from a mixture of methanol and water the product melts at l75-l77 C.

EXAMPLE 29 Tablets containing 100 mg. of active substance are prepared, for example with the following ingredients:

Method The N,N'-di- ['y- (2-methyl-6-dirnethylamino-pyrimidyl- 4-amino)-propyl]-piperazine is mixed with the lactose, a part of the wheat starch and with colloidal silicic acid and the mixture passed through a sieve. The remaining wheat starch is pasted with 5 times the quantity of water on a water-bath and the powdery mixture kneaded with this paste until a slightly plastic mass is formed. The plastic mass is passed through a sieve having a mesh of about 3 mm., dried and the dry granulate passed again through a sieve. Arrowroot, talc and magnesium stearate are then mixed in and the resulting mixture compressed into tablets weighing 250 mg.

What is claimed is:

1. A member selected from the group consisting of a compound of the formula Alk" RAN/ R1 in which R and R each is a member selected from the group consisting of hydrogen and lower alkyl, R R R and R R and R are members selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkoxy-lower alkyl, lower alkenyloxylower alkyl, lower alkoxy, lower alkenyloxy, lower alkoxy-lower alkoxy, hydroxy, free amino, and amino substituted by at least one member selected from the group consisting of lower alkyl, lower alkenyl, cyclo-lower alkyl, cycle-lower alkenyl, cyclo-lower alkyl-lower alkyl, cyclo-lower alkyl-lower alkyl and -lower alkenyl, cyclolower alkenyl-lower alkyl and -lower alkenyl, each of said cyclo-lower alkyl and cyclo-lolwer alkenyl moieties having 5 to 6 carbon atoms, oxa-lower alkylene and azalower alkylene, and R and R and R and R taken together are lower alkylene, Alk, Alk', Alk" and Alk each represents lower alkylene which separates the nitrogen atoms by at least two carbon atoms; their N-oxides and therapeutically acceptable acid addition salts thereof.

2. A compound as claimed in claim 1, said compound being a member selected from the group consisting of a compound of the formula in which at least one of the radicals R and R and at least one of the raicals R and R each represents a member selected from the group consisting of free amino, monoand di-lower alkylamino, pyrrolidino, piperidino, piperazino, N-lower alkyl piperazino and N-hydroxylower alkyl piperazino, whereas the others of these radicals are members selected from the group consisting of hydrogen, lower alkyl and lower alkoxy-lower alkyl, symbols R and R represent members selected from the group consisting of hydrogen, lower alkyl and lower alkoxy-lower alkyl and the symbols Alk and Alk' represent alkylene-(l, 1) having 2 to 6 carbon atoms; and therapeutically acceptable acid addition salts thereof.

3. A compound as claimed in claim 2, in which at least one of the radicals R and R and at least one of the radicals R and R represent a member selected from the group consisting of monoand di-lower alkylamino and the others of these radicals have the meaning iven in claim 2.

4. A compound as claimed in claim 1, said compound being a member selected from the group consisting of a compound of the formula Il\TH-Alk"-N N-Alk -Nfl l i Ra -k /-R1 Ri -k /-R1'" in which R and R each represents a member selected from the group consisting of free amino, monoand dilower alkylamino, pyrrolidino, piperidino, morpholino, piperazino or N-lower alkyl and N-hydroxy lower alkylpiperazino, R and R each represents a member selected from the group consisting of hydrogen and lower alkyl, and Alk" and Alk' each represents a member selected from the group consisting of propylene-(1,2), propylene-(2,3), ethylene-(1,2) and propylene-(1,3), and therapeutically acceptable acid addition salts thereof.

5. A compound as claimed in claimp4, in which R and R each represents a member selected from the group consisting of monoand di-lower alkylamino and the other symbols have the meaning given in claim 4.

6. A compound as claimed in claim 1, said compound being a member selected from the group consisting of N,N' di ['y (6 methylamino 2 methyl pyrimidyl- 4-amino)-propyl]-piperazine, and therapeutically acceptable acid addition salts thereof.

7. A compound as claimed in claim 1, said compound being a member selected from the group consisting of N,N' di ['y (6 amino 2 methyl pyrimidyl 4- amino)-propyl] -piperazine, and therapeutically acceptable acid addition salts thereof.

8. A compound as claimed in claim 1, said compound being a member selected from the group consisting of N,N di ['y (6 dimethylamino 2 methyl pyrimidyl 4 amino) propyl] piperazine, and therapeutically acceptable acid addition salts thereof.

9. A compound as claimed in claim 1, said compound being a member selected from the group consisting of N,N' di [6 (6 dimethylamino 2 methyl pyrimidyl 4 amino)-butyl]-piperazine, and theapeutically acceptable acid addition salts thereof.

ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner US. Cl. X.R. 

